Pharmaceutical compositions for alleviating discomfort

ABSTRACT

The invention relates to products for complete nutrition of infants or diseased or elderly persons. The products are characterized by increased levels of folic acid, vitamin B6 and vitamin B12 or their functional equivalents. These products improve feelings of well-being of infants, especially those of young age, and are useful in the treatment and prevention of diseases that are associated with disorders of serotonin and melatonin metabolism.

FIELD OF THE INVENTION

The invention is related to pharmaceutical and/or nutritionalcompositions, including infant formulae, for improving feelings ofwell-being, compensation of immaturity and problems in the metaboliccapacity. The nutritional products provide complete nutrition toinfants, diseased and elderly people, and their composition ischaracterised by increased amounts of cofactors. The nutritionalproducts can also be in the form of supplements that provide thecofactors and only a part of the further desirable food components.

BACKGROUND OF THE INVENTION

At present a large part of the population of babies in industrialisedcountries are fed with specialised infant formulae. It has been reportedthat consumption of these formulae is associated with several medicalproblems, such as increased frequency of gastrointestinal problems anddecreased immune status. Such problems may occur at young age, butperhaps also at later age, because infants that are exclusively fed withhuman breast milk would score better on these parameters. It has alsobeen reported that infants that are exclusively fed with theseartificial formulae suffer from longer episodes of crying compared tothose that are fed with human breast milk. This suggests a generalfeeling of discomfort due to perhaps hunger, pain or even medicalproblems. These problems may delay development of the child and produceconcerns and practical problems to the parents.

In a first aspect of the invention it is aimed to develop a new infantformula for complete nutrition that decreases the number of cryingepisodes and promotes sleeping behaviour for the child, especially forinfants of young gestational age.

In a second aspect it is also aimed to develop infant formulae thatcompensate for the relatively small capacity of the (rapidly developing)metabolic systems of the child shortly after birth. This leads toimproved health, formation of higher quality new tissue (visual acuity,intellectual capacities, etc.), a better immune status and a decrease inoccurrence of periods of increased bilirubin plasma levels(hyperbilirubinaemia or jaundice). Increased bilirubin levels are knownto occur relatively often within the first 3 weeks after birth. Some ofthe negative effects of this disorder have been described in the priorart, including the inhibition by bilirubin of the uptake of theneurotransmitters dopamine and glutamate by the synaptic vesicles andthe neurotoxic effects that this disease state may have.

Conventional infant formulae have been developed that mimic thecomposition of human breast milk to a degree that can be achieved at areasonable price. These formulae are normally based on cow's milkproteins like casein or mixtures of casein and whey. In case ofproblems, such as metabolic disorders or allergic reactions, otherprotein sources are used like hydrolysates or soybean proteins;alternatively the allergic component is replaced by anothernon-allergenic ingredient. However, the composition of these formulaestill differs from that of human breast milk. The relatively low levelsof tryptophan and cysteine/cystine can be compensated for by increasingthe amount of protein in the product. However, this increases the amountof threonine to very high levels and increases the costs of theformulae. Also the imbalances with regard to the ratio of tryptophan tothe sum of the large neutral amino acids will be maintained.

In a further aspect, the invention is related to the use of folic acid,vitamins B12 and B6 or their functional analogues in the manufacture ofcompositions for the prevention and/or treatment of specificneurological disorders. The invention also covers the products that areobtained by such use. Products according to the invention will beeffective in improving sleep behaviour, insomnia, mood, decreasefeelings of fear and depression and increase feelings of wellbeing. Inaddition, undesirable symptoms related to neurodegenerative disorderslike Alzheimer, Parkinson and schizophrenia are decreased. Also, theproducts can be helpful in the prevention and/or treatment of symptomsassociated with restless legs syndrome, myoclonus (a disorder that isoften accompanied by muscle contractions and seizures), Gilles de laTourette, phenylketonuria, multiple sclerosis, analgesia, epilepsy,mania, aggressive behaviour, bulimia and other disorders associated withsaturation feelings after eating, ADHD, and psychiatric disordersassociated with ageing. Large parts of the population suffer from one ofthese disorders. Application of common drug therapy may result inundesired side effects, such as addiction and ineffectivity, and maylead to functional deficiencies of food components. So there is a needfor a pharmaceutical or nutritional formulation that helps prevent ortreat these disorders and does not result in these side effects.

Sandyk, R., reported in Intern. J Neuroscience, 1992, 67, 127-144 thatseveral, but not all, of these disorders were associated with decreasedserotonin levels in the brain and reviewed some of the relevantliterature about the use of tryptophan to restore serotonin levels inthe brain.

We believe, however, that all these disorders are associated not onlywith a disorder in serotonin levels, but also with the melatonin levelsin the brain, the presence of pterines and folate in the brain and thefunctioning of the methylating system in the body. The latter may becomeevident by abnormal systemic adenosine levels. Because relatively verylittle serotonin or melatonin is present in the normal diet, mostendogenous amounts must originate from biosynthesis. An increase in thebrain levels of both serotonin and melatonin can therefore only beachieved by increasing the metabolic capacity of the serotoninergicneurons. An increase of the brain levels of both serotonin and melatoninand the presence of reduced folic acid and pterins in the brain wouldlead to a relief of the clinical problems.

Sandyk disclosed that in some cases administration of an effectiveamount of the natural precursor of serotonin, tryptophan, could lead toincreased levels of serotonin in brain tissue. This idea was alsosubject of a number of other publications, which appeared in the past.

WO 87/01590 (=EP-A-238533, Kreitzman) discloses a slimming diet foradults that provides per day less than 1000 kcal (so less than 14kcal/kgbw.d; less than 700 kcal/day is preferred), less than 100 gprotein (which results in less than 1.4 g protein per kgbw per day for a70 kg person; always more than 30 g and less than 46 g protein ispreferred) and more than 0.5 g tryptophan (more than 3 g is preferred).The product is unsuitable for feeding infants due to too high proteinlevels and potential toxicity of the amount of tryptophan that isincluded. The product should also not be used for combating obesity ofthe infant.

EP-A-007691 (Wurtman) discloses a formula for suppression of appetitefor carbohydrates in adults, which comprises tryptophan, in an amount of10-100 mg per kgbw.d, and carbohydrates, but no branched-chain aminoacids. The ratio of the amounts of tryptophan and carbohydrates in theformula must be 1: 3-50. The product is unsuitable for use in infants,because infants require branched chain amino acids at young age forgrowth.

WO 91/10441 (=EP-A-463154) discloses compositions comprisingpolypeptides containing more than 2.2% tryptophan as well as arginine orornithine for providing a “serotinergic effect”. The product isdeveloped for combating obesity in adults and treating feelings ofdepression. Preferably α-lactalbumin is used as a source of tryptophan,which possesses a high ratio of tryptophan to large neutral amino acidsplus methionine. Vegetable proteins are suggested as attractiveingredients, because of their relatively high amount of arginine andrelatively low levels of phenylalanine and tyrosine. The latter twoamino acids are however essential amino acids and recommended dailyintakes should be ensured.

WO 98/14204 discloses the use of α-lactalbumin as nutritional complementor medicine for regulating sleep, especially when a jet lag is observed.Consumption of 100 mg and 250 mg α-lactalbumin is claimed to beeffective in adults. No relation is made to use in infants nor isindicated that vitamins might play a role in regulating sleep.Alpha-lactalbumin was shown to have a value of the ratio of tryptophanto the sum of the large neutral amino acids is about 0.074 and that ofthe ratio Cys to Trp equals about 1.47, while the amount of tryptophanis relatively high (about 3.0%).

Heine discloses the use of hydrolysed α-lactalbumin as protein source ininfant formulae in DE-A-4130284. Use of this protein hydrolysate wasclaimed in order to achieve a clear separation with β-lactoglobulin andthus administer a better-balanced composition with regard to threonine,tryptophan and cysteine/cystine. No reference was made to specificpositive effects that can be obtained by using intact α-lactalbumin withregard to feelings of well-being nor the support of insufficientlyfunctioning metabolic systems by using the products of the invention. Noindication is given that folic acid, vitamin B12 and B6 play a crucialrole in these respects. The products disclosed by Heine are also moreexpensive and have a worse taste compared to the products of the presentinvention.

After consumption of carbohydrates, insulin is released from thepancreas. This latter component is known to reverse the catabolicprocesses in the body, that may have resulted from a period ofstarvation prior to the (re)feeding of the child, into anabolicprocesses. As long as sufficient glucose is present in the plasma,plasma insulin levels remain sufficiently high to prevent catabolism of(in particular muscle) tissue and the resulting release of branchedchain amino acids (BCAA, valine, isoleucine and leucine). In a furtheraspect, the invention is therefore aimed at developing formulae thatprovide an insulin response on a short term, with a sufficientlonger-term effect as well.

Infants, especially those of young gestational age, are extremelysensitive to consumption of excess amounts of food components andimbalances in the consumption pattern of these components, predominantlydue to their low relatively metabolic and clearance capacity. This iscaused by inherited problems and immaturity of their enzymatic systemsand the small capacity of their organs. Infants are also sensitive toimbalances in neurotransmitter levels in the brain. It is thereforedangerous to transfer concepts that are developed for healthy adults toinfant formulae. The composition of human breast milk is thereforemostly taken as “golden standard”. In another aspect of the invention, anutritional product is aimed at that does not cause any toxic reactionsin normal use and to deviate as little from the golden standard as isjustified.

It is important to recognise that all the aspects as mentioned abovemust be achieved at the same time, in order to improve well-beingsatisfactorily without causing negative effects to the child. Alsoelderly people may suffer form an imparted metabolic capacity andespecially the group having neurodegenerative disorders should not beexposed to inbalanced food.

According to the prior art, relatively high doses of tryptophan have tobe administered, optionally in the relative absence of large neutralamino acids and accompanied with digestible carbohydrates, in order tosee clinical benefits. This approach leads to several problems. In somepatients no or very little effect is observed. Administering high dosesof tryptophan may lead to undesired side-effects, especially in thosepatients that have a low metabolic capacity or are deficient in certainvitamins or minerals. Examples of these patients are persons that are atrisk for or are suffering from diabetes mellitus or bladder cancer,persons that are subjected to drug therapy, persons suffering of renalproblems, young infants and elderly persons. Also, it appeared to bevery difficult to estimate for a particular person the exact requirementof tryptophan for obtaining optimal serotonin levels and it is unknownhow high these desirable serotonin levels are.

It has now been found that the restoration of the patient's capacity tometabolise tryptophan to serotonin and especially melatonin, is anapproach that does not demonstrate the above-mentioned disadvantages. Itallows the natural mechanisms to regulate endogenous levels, withoutsubjecting the organism to high levels of potentially toxic tryptophan.

This can be achieved by administering extra amounts of certaincofactors, at least folic acid, vitamin B12 and vitamin B6. In thissituation it is often not required to supplete tryptophan; however, inthose cases that persons are deficient in tryptophan, administration ofrelatively little amounts of tryptophan already gives significantimprovement of the clinical symptoms.

In cases where a patient has a limited capacity for serotoninbiosynthesis, e.g. by damage to tissue that is rich in serotoninergicneurons or due to an inherited disorder, administration of cofactorsappeared to increase serotonin and melatonin levels in the brain, if acertain basal level of tryptophan was available.

It was found that the cofactors of interest are at least folic acid,pyridoxal phosphate and vitamin B12 or their functional equivalents. Inaddition it may be required to administer riboflavin, thiamine andniacin, or their functional equivalents.

The biochemical roles of folic acid, vitamin B6 and B12 are described inthe art. To the best of the knowledge of the inventors, it is nowheredescribed or indicated that consumption of the combination of thesevitamins, in amounts as given in the claims, is crucial for increasingwell-being and normalising behaviour, senses of pain, and mood of theinfant, and elder persons. It was found that the restrictions in proteinand carbohydrates composition, that are present for infant formulae,necessitate the increase in these vitamins in order to have an optimaleffect. It is also not earlier disclosed that inclusion of thesevitamins in the amounts as claimed, significantly enlarges the group ofinfants that benefit from such infant formulae, especially with regardto increase of well-being, the improvement of other serotonin ormelatonin-mediated disorders.

Also, the amounts of all three essential vitamins, being folic acid,vitamin B6 and B12 are insufficient to support biosynthesis andmetabolism, including the serotonin metabolism, in the young child.

DETAILED DESCRIPTION OF THE INVENTION

The characteristics of the composition according to the invention aredescribed in the claims and in more detail below. For optimaleffectivity at least 200 μg folic acid, at least 1.9 μg vitamin B12 andat least 0.3 mg vitamin B6 is required per daily dosage, and preferablyat least 300 μg, at least 4.8 μg and at least 3.0 mg of respectivelyfolic acid, vitamin B12 and vitamin B6.

In most cases also at least 0.5 mg riboflavin (vitamin B2), 1.0 mgthiamine (vitamin B1) and at least 2 mg niacin per daily dosis isrequired. Deficiencies on the latter components occur relatively oftenin the above-mentioned groups of patients and these will lead toimparted generation of ATP and reducing power in the form of NAD(P)H.Riboflavin is also required for activating pyridoxal. Low ATP levels aredeleterious to the metabolic capacity to methylate and the biosyntheticcapacity for melatonin and serotonin.

It is further highly desirable that digestible carbohydrates that canserve as glucose source are included in the product. Examples areglucose polymers, lactose and sucrose. This ensures a continuous supplyof reducing equivalents in the form of NADH and improves in someinstances the transport of tryptophan from blood into the brain. Aproduct according to the invention should advantageously comprise atleast 5 g digestible carbohydrates and preferably more than 10 g on adaily basis. Per 100 kcal (419 kJ) of product, the amount of digestiblecarbohydrate is in the range of 4-25 g, preferably 6-22 g.

The product should further preferably comprise magnesium to improvemethylation, and zinc to improve total metabolism of sulfur amino acids.Magnesium also stabilises the NMDA receptor. An overstimulation of theNMDA receptor is associated with many of the above-mentioned disordersand maintenance of an overstimulation of this receptor is claimed toaggravate some of the symptoms that are observed in some of thesediseases. Zinc is further involved in the modulation of neurotransmitterreceptors. Zinc should best be above 0.7 mg/100 kcal, which results in adaily intake of at least 3.6 mg. Magnesium should best be included in anamount of at least 5 mg/100 kcal, leading to a daily consumption of atleast 36 mg. On the other hand, the amounts of calcium and phophorusshould not be too high. Specifically, the weight ratio of Mg+Zn to Cashould be more than 0.08, preferably more than 0.10, and the weightratio of Mg+Zn to P should be more than 0.2, preferably more than 0.26(and Ca+Mg+Zn/P>1.9).

Tryptophan can be included in an amount of 0.05-3 g per daily dose, inparticular 0.3-1.2 g. Preferably tryptophan is supplied in the form of aprotein. The protein must have an amino acid composition that ischaracterised by a high ratio of tryptophan/large neutral amino acids,preferably in the range of 0.048-0.2. Alfa-lactalbumin was found to be asuitable protein.

It is also advantageous to include melatonin in the product, especiallyin those products that are meant to be used in the evening. Melatoninupregulates certain enzymes that play an important role in thedetoxification of radicals that are created in the highly firing neuronsand that may play a role in the pathogenesis of the disorders mentionedabove. Melatonin also can help to set and regulate the circadian rhythm,which can be very helpful in the treatment of sleeping disorders anddepression. Melatonin can be included in an amount of 0.5-5 g per dailydosage.

Also adenosine can be used to set the circadian cycle; an amount of50-1000 g per daily serving is recommended.

Betaine, choline, methionine or their functional equivalents should beincluded in those situations that is suspected that the patient suffersfrom a lack of food components that provide methyl groups. Examples arethe elderly or schizophrenic patients that often have very poor eatingbehaviour. Betaine is the preferred source because it also can serve asa precursor for choline that is useful for synthesis or myelin or repairof damaged neurons and because it has an excellent taste. Obviously alsocholine itself can be used. Betaine can be included in an amount of30-4000 mg and preferably 50-600 mg per daily dosage.

Methionine can be included in an amount of 50-1000 mg and preferably100-500 mg per daily dosage. Vitamin K (phylloquinones, menaquinones andother naphtho-quinones) or its functional equivalent is preferablyincluded at a level of at least 8 μg, preferably at least 30 μg per 100kcal. For elderly persons, a daily minimum of 1 mg is found to bebeneficial.

Other minerals, trace elements and vitamins can be included in amountsthat comply with the recommendations as set by the National ResearchCouncil (US) or other official institutes.

The preferred amounts of all components depend on the group of patientsfor which the product is developed. Young infants would normally requirelower amounts than adults; elderly suffering from a severe form ofAlzheimer would normally benefit from less of the active components thana young adult that is suffering from the syndrome of Gilles de laTourette.

Typical amounts per 100 kcal of the product are summarised in Table 1.

TABLE 1 Amounts per 100 kcal product Component Range Preferred rangeDigestible carbohydrates 4-25  6-22 g Folic acid 44-4000  50-2000 μgVitamin B12 0.8-2000    1-1000* μg Vitamin B6  50-10000  60-2000 μgRiboflavin 0.08-20    0.14-6    mg Thiamine 55-8000  70-4000 μg Niacin0.55-60    1.4-25   mg niacin equivalents Vitamin K >8 30-90  μg Taurine5-100 7-50 mg Betaine 50-4000 30-600 mg Magnesium 5-400  8-200 mg Zinc0.8-100   1-30 mg Mg + Zn/Ca >0.08 >0.10 m/m Mg + Zn/P >0.20 >0.26 m/mMelatonin 30-3000 60-800 mg Tryptophan 0.05-8    0.2-2*  g Adenosine 1-1000 50-500 mg Methionine 50-1000 100-500  mg Note *higher dosesshould preferably be given as a multifold of smaller doses.Infant Formulae

Energy density: The energy density of the product is similar to that ofprior art products and is in the range of 62-73 kcal/100 ml liquid orreconstituted product. Preferably the energy density is in the range of64-71 kcal/ml.

Proteins: Protein levels in a product can be determined with theclassical Kjeldahl method. The result reflects the crude proteins thatare present. For the purpose of this invention we define the proteinlevel as the amount of real proteins plus the amount of amino acids,their salts and peptides; so non-protein nitrogen is excluded. In theproducts of the invention the protein levels will be in the range of1.0-3.0 g per 100 kcal, especially between 1.0 and 2.4 g/100 kcal, whichallows complete satisfaction of the infants protein needs. An amount of1.5-2.2 g/100 kcal is most preferred. The higher protein levels, such asfrom 2.0 or from 2.4 to 3.0 are especially suitable in combination withincreased levels of folic acid, vitamin B6 and/or vitamin B12.Conventional proteins like those from cow's milk or soybeans can be usedas basic protein sources, as they provide sufficient amounts of allessential amino acids but also branched-chain amino acids.

In order to increase the amount of L-tryptophan in the product, freeL-tryptophan, or a functional equivalent thereof like tryptophan saltsor tryptophan-rich peptides, can be suppleted. If free L-tryptophan isused, special care is taken to remove all impurities that might causetoxic reactions. It is further preferred to use a tryptophan source thatis stable under the conditions that the infant formula is manufactured.A suitable source is a tryptophan-rich protein or a hydrolysate orextract thereof. If proteins are used as ingredient, it is obvious thatthe levels of the large neutral amino acids (Tyr, Phe, Val, Leu, Ile)and threonine are relatively low. However they should not be that low,that the recommended daily intakes are not met. Examples of suitableproteins in this respect are acid whey, α-lactalbumin, egg protein andproteins from meat and wheat, and mixtures of two or more of thesecomponents. Acid whey protein or unhydrolysed α-lactalbumin areespecially preferred, because of the excellent amino acid profile andthe sustained release pattern in young children compared to hydrolysatesthereof or compared to a combination of mixtures of alternative dairyproducts and suppleted sources of tryptophan, cysteine or arginine.Tryptophan should be present in the product in an amount of 1.6-3.5 g,especially 1.7-3.5 g per 100 g of the total protein component andpreferably in an amount of 1.9-2.8 g/100 g protein.

The value of the ratio of the amounts in the product of tryptophan andthe sum of the large neutral amino acids must be in the range 4.8-10 andpreferably in the range 5.5-8.5/100, and most preferably 6.2-8.2/100.When threonine is also considered as a large neutral amino acid, thevalue of the ratio must be in the range 4.1-8.0 and preferably in therange 4.7-7.5.

In order to ensure sufficiently high levels of cysteine, whey proteinsor egg proteins can be included in the formula. If whey proteins areused, acid whey is recommended, in order to avoid too high threoninelevels. It is especially preferred to have a relatively high ratio ofCys/Trp in the range of 0.8-1.4, in order to support optimally inclusionof cysteine in liver proteins and in glutathione, which is required foroptimal growth and immune function.

In order to increase insulin response arginine or lysine can be suppliedas L-forms of the free amino acid or as their functional equivalents.Functional equivalents of amino acids can for example be their salts,synthetic peptides, or proteins that are rich in the particular aminoacid, or extracts or hydrolysates of these proteins. Also mixtures ofproteins can be included. For example mixtures of 40% casein and 60%whey could be suppleted with the hydrochloric salts of L-tryptophan orL-arginine. It is however preferred to include arginine in a form thatis slowly released such as by using a granulate or similar system thatcomprises an arginine salt like L-arginine.HCl, or by using partiallypea protein, or a hydrolysate or extract thereof, in order to extend theinsulin effect. The total amount of arginine plus lysine should exceed200, preferably exceed 250 mg/kg, e.g. 280 mg/kgbw.d. The amount ofprotein that is required for providing this amount of arginine can becalculated from this number and the concentration of arginine or lysinein this protein.

Carbohydrates: According to the invention, the amount of carbohydratesin the formula must be in the range of 9-15 g/100 kcal (35-60 en %), andpreferably in the range of 11-14 g/100 kcal. This results in acarbohydrate content of 5.7-10.5 g per 100 ml of liquid or reconstitutedproduct. The ratio of the amount of carbohydrates to the amount oftryptophan will exceed 20 and preferably 50, and go up to 940,preferably up to 450. The weight ratio of carbohydrates to protein ispreferably from 5 to 14, most preferably from 6 to 12.

It is preferred to use, at least partly, maltodextrins, apart from thelactose that may be present in the formula. This will ensure a fastavailability of glucose units in plasma and therefore a fast insulinresponse. However, it is preferred to include at least 50% of thecarbohydrates as lactose, except in those cases that the product will beused by lactose-intolerant infants. If maltodextrins are used it isadvantageous to use maltodextrins having a degree of hydrolysis of 10-15dextrin equivalents, in order to decrease the sweetness of the product.

Folic acid: Folic acid can occur in nature in many forms. Typically itis suppleted to infant formulae as monoglutamate. Though according tothe invention basically all functional equivalents of folic acid can beused, it is preferred to use the monoglutamate form for obtaining bestbioavailability. It is essential to include at least 44 μg per 100 kcal.If higher amounts of folic acid are consumed, a larger group of infantswill show an improved serotonin- and melatonin metabolism, even if theamounts of tryptophan are relatively low as in conventional infantformulae. This is especially true if the amount of folic acid is above50 μg per 100 kcal and sufficient vitamin B12 is made available, as isthe case when the formula is suppleted with more than 0.6 μg/100 kcal,as is indicated below.

Vitamin B12: Vitamin B12 is normally present in infant formula partiallyas a complex with dairy proteins and predominantly as suppletedcyanocobalamine. Before it is absorbed the complex has to be split inthe stomach and the released cyanocobalamine has to bind to a factorthat is released from the stomach. Once absorbed, cyanocobalamine oralternative forms have to be converted to methylcobalamine, before theycan be used as a cofactor that catalyses the conversion of homocysteineto methionine. Both absorption and conversion of cyanocobalamine occurineffectively in part of the population of young infants.

According to the invention it is therefore required to supplete at least0.1 μg, and preferably more than 0.8 μg vitamin B12 per 100 kcal,preferably as hydroxycobalamine or a stabilised form, in order tosupport serotonin biosynthesis and metabolism effectively. Instead ofvitamin B12, metabolic equivalents, i.e. compounds that lead toendogenous formation of vitamin B12, can also be used.

When indigestible carbohydrates are added to the product or otherbifidogenic measures are taken, these are selected in such a way thatthe biosynthesis capacity of the gut flora is not imparted or even isstimulated.

Vitamin B6: Vitamin B6 is active in the cells as pyridoxal phosphate.However pyridoxine or pyridoxamine are frequently used as source of thisvitamin, because of the stability of these compounds. Infants,especially those of young age, have a restricted capacity to convertthese compounds to the active form. It has been found that a simpleincrease in the dose may decrease the intracellular pyridoxal phosphatelevels. It is therefore preferred to include in the formula 50-130 μgvitamin B6 per 100 kcal. If higher amounts of vitamin B6 are suppleted,it is not recommended to use pyridoxine. Also mixtures of pyridoxamineor pyridoxal can be used.

Zinc: It is desirable that the amount of zinc is in the range of 0.7-2mg/100 kcal, preferably from 0.7 to 1.0 mg/100 kcal. Zinc can beincluded as a zinc salt, such as zinc chloride or as a complex withamino acids or other components.

Niacin equivalents: Niacin functions in the human body as precursor ofNAD and can be synthesised from tryptophan in the adult liver. Thispredominantly occurs when excess tryptophan is present. Thus tryptophancan also be used as a niacin equivalent (60 mg Trp=1 niacin equivalent).Biosynthesis of niacin is supported in the young child by thecharacteristic features of the composition as claimed. This permits theavailability of sufficient niacin to support the metabolic processes inthe child. These can be further supported by increase of the includedamount of niacin to a level of 1.2-5 mg/100 kcal.

Apart from the essential components as indicated above, othermicroingredients may advantageously be included in a complete infantformula, according to EEC 91/321 or corresponding Regulation: theseinclude: Betaine, choline; taurine, inositol, calcium, phosphorus,magnesium, iron, manganese, copper, iodine, sodium, potassium, chloride,selenium, fluoride, carnitine, nucleotides, cholesterol, vitamin A, vit.D, vit. E, vit K, thiamine, riboflavin, pantothenic acid, biotin, andascorbic acid.

Fats are included in the range of 40-57 en %. The composition of the fatcan be selected from prior art compositions. Specially preferred are theones that are disclosed in any of the earlier patents of patentee, e.g.EP-A404058, EP-A-231904, EP-A-784437 and DE 19644518, which areincorporated by reference. The essential fatty acids that are presentmust preferably have the cis-configuration. Alpha-linolenic acid (=ALA):1.75-4.0% and linoleic acid (LA): 8-35% of total fatty acids; the ratioLA/ALA=5-16.

The product of the invention can have the form of liquid or a powder,that can be reconstituted with water to produce a ready to feedformulation. It can also have the form of a meal that is used forweaning purposes or similar product evident to a person skilled in theart. The liquid products can be packaged in bottles, cartons and thelike. The powdered products can be packaged in vacuumised packs, cans orsachets and other suitable forms that are known to a person skilled inthe art.

It has been found that daily consumption of the infant formulae asdescribed above results in the benefits as described below:

-   -   improves feelings of well being by the infants,    -   supporting regular eating and sleeping patterns    -   helps to compensate for insufficient capacity of the metabolic        systems, especially in the young infant    -   consumption of these formulae results in plasma levels of amino        acids that are more similar to those of infants, that are        exclusively fed with human breast milk, compared to consumption        of conventional formulae    -   does not give negative side effects to the infant    -   therefore improves health and immune status and supports growth        of high quality    -   has an excellent taste and can be produced at acceptable costs.

EXAMPLES Example 1

A liquid infant formula having the composition as presented in table 2was prepared.

TABLE 2 Composition of liquid infant formula Values are in mg per 100ml, except where indicated differently. Protein (60% sweet whey, 40%casein) 1400 Added Trp 10 Added Arg 10 Lactose 7500 Maltodextrins (10-15DE) 1600 Fat (EP-231904) 3100 Na 18-25 K 60-100 Cl 40-60 Ca 50-85 P20-50 Mg 4.5-6 Fe 0.5-0.9 Zn 0.6-1.3 Cu 40-60 μg Mn 5-20 μg Se 1.5-2.2μg I 5-15 μg Vitamin A 80-90 RE β-Carotene 0-40 μg Vitamin D 1-1.6 μgVitamin E 0.8-1.4 mg TE Vitamin K 4-20 μg Thiamine 35-45 μg Riboflavin110-150 μg Niacin 0.7-1.0 mg NE Pantothenate 0.25-0.35 Biotin 1.5-1.7 μgAscorbic acid 5-10 Taurine 4-7 Folic acid (added as monoglutamate) 25-32μg Vitamin B12 (added as hydroxycobalamine) 0.4-0.7 μg Vitamin B6 (addedas pyridoxine) 50-65 μg

This product can be used for improving sleeping behaviour of younginfants.

Example 2

Product to be used for the elderly or toddlers as a bedtime drink:

Powdered supplement packed in a can under nitrogen; 10 g to bereconstituted in fruit juice or milk before going to bed.

To 8 kg maltodextrin DE19 are added:

-   -   2.0 kg alfa-lactalbumin    -   50 mg melatonin    -   100 mg folic acid monoglutamate    -   25 mg cyanocobalamin    -   100 mg pyridoxal    -   100 mg riboflavin    -   60 mg thiamine.HCl    -   30 g zinc chloride.12H20

A proper aliquot is filled in the can, e.g. 400 g.

Example 3

Product to be used for ADHD infants or Alzheimer patients.

Powdered product packed in a 10 g sachet. The sachet is to be mixed witha portion of breakfast cereal and reconstituted in milk.

The powder is obtained by mixing:

-   -   9.5 kg Maltodextrin    -   100 mg folic acid    -   25 mg vit. B12    -   100 mg B6    -   100 mg B2    -   60 mg B1    -   1.0 g niacin    -   100 g betaine    -   300 g magnesium chloride    -   30 g zinc chloride    -   50 g adenosine    -   100 mg Vitamin K

1. A composition, comprising carbohydrates, fats and proteins, andcontaining more than 44 μg up to 4000 μg of folic acid, more than 0.8 μgup to 2000 μg of vitamin B12 and more than 50 ug up to 10,000 μg ofvitamin B6 per 100 kcal of said carbohydrates, fats and proteins, andfurther containing at least one of riboflavin, thiamine, niacin andzinc.
 2. A method for treating serotonin- or melatonin-mediated mood orsleep disorders, comprising administering to a person in need of suchtreatment a composition for complete nutrition comprising carbohydrates,fats and proteins, the composition further containing an effectiveamount of a combination of more than 44 μg up to 4000 μg of folic acid,more than 50 μg up to 10,000 μg of vitamin B6 and more than 0.8 μg up to2000 μg of vitamin B12 per 100 kcal of said carbohydrates, fats andproteins and at least one component selected from the group consistingof riboflavin, thiamine, niacin and zinc.
 3. The method according toclaim 2, in which the composition is a composition for completenutrition of infants.
 4. The method according to claim 2, in which thecomposition is a composition for complete nutrition of diseased orelderly persons.
 5. The method according to claim 2, in which thecomposition further contains at least 0.55 mg of niacin and/or at least0.08 mg of riboflavin and/or at least 55 μg of thiamine per 100 kcal. 6.The method according to claim 2, in which the composition furthercontains more than 50 mg of choline or betaine or the sum thereof,and/or at least 5 mg of taurine, and/or at least 50 mg of methionine per100 kcal.
 7. The method according to claim 2, in which the compositionfurther contains 0.05-8 g of tryptophan and/or 30-3000 mg of melatoninand/or 50-1000 mg of adenosine per 100 kcal.
 8. The method according toclaim 2, in which the composition further contains 5-400 mg magnesiumand/or 0.7-100 mg zinc per 100 kcal, and calcium, and having a weightratio of magnesium plus zinc to calcium of higher than 0.08.
 9. Themethod according to claim 2, in which the composition contains 9-15 g ofcarbohydrates per 100 kcal.
 10. The method of claim 2, comprisingadministering an amount of at least 200 μg of folic acid, at least 2 μgof vitamin B12 and at least 2 mg of vitamin B6 per daily dosage.